Potential Value of Biomarker-Based Approaches for Evaluation and Management of Costly Functional Gastrointestinal Diseases
Authors: Michael Camilleri, Joelle BouSaba
Journal: Clinical Gastroenterology and Hepatology (2023)

Functional gastrointestinal disorders including irritable bowel syndrome (IBS) are costly diseases associated with significant direct and indirect costs. This treatise deals predominantly with IBS, and we apply the same principles to another example, functional dyspepsia. Strategies to control direct expenditure in IBS were proposed over 2 decades ago1Camilleri M. Williams D.E. Economic burden of irritable bowel syndrome. Proposed strategies to control expenditures.Pharmacoeconomics. 2000; 17: 331-338Crossref PubMed Scopus (97) Google Scholar and include the education of physicians that manage patients with IBS, education of the patients themselves, introduction of psychological treatments, and addressing psychosocial issues early in the management process, curtailing unnecessary investigations, and developing effective doctor–patient relationships.2Drossman D.A. Chang L. Deutsch J.K. et al.A review of the evidence and recommendations on communication skills and the patient-provider relationship: a Rome Foundation working team report.Gastroenterology. 2021; 161: 1670-1688.e7Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Since then, there has been significant documentation regarding the direct and indirect costs associated with IBS. A prior study evaluated the cost-effectiveness of tests for diarrhea-predominant IBS (IBS-D), but the biomarker tests pertained to investigations to exclude alternative diagnoses, rather than to focus on biomarkers related to the etiopathogenesis of the IBS.3Almario C.V. Noah B.D. Jusufagic A. et al.Cost effectiveness of biomarker tests for irritable bowel syndrome with diarrhea: a framework for payers.Clin Gastroenterol Hepatol. 2018; 16: 1434-1441.e21Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Since that report in 2018, there has been significant advance in the identification of biomarkers and potentially therapeutic reversal of the related mechanisms. The purpose of this review is to introduce the potential of biomarker-based approaches for the evaluation and management of IBS as an alternative to sequential therapeutic trials as proposed in recent guidelines. There are several lines of evidence that document the high cost associated with IBS. First, a study from the United Kingdom4Goodoory V.C. Ng C.E. Black C.J. et al.Direct healthcare costs of Rome IV or Rome III-defined irritable bowel syndrome in the United Kingdom.Aliment Pharmacol Ther. 2022; 56: 110-120Crossref PubMed Scopus (25) Google Scholar has documented direct healthcare costs of Rome IV– or Rome III–defined IBS. Thus, the mean annual direct cost of IBS per person among 752 patients with Rome IV IBS was £556.65 ± 1023.92, and for 995 patients with Rome III IBS, the mean annual direct cost was £474.16 ± 897.86. It was also estimated that the annual direct healthcare cost of IBS in the United Kingdom is £1.27 billion (Rome IV IBS) and £2.07 billion (Rome III IBS). In fact, among patients with Rome IV IBS, mean annual costs were higher in those with opiate use (£907.90 vs £470.58; P < .001), more severe symptoms (P < .001 for trend), shorter duration of IBS (1 year: £1227.14 vs >5 years: £501.60; P = .002), lower quality of life (P < .001 for trend), and higher depression, somatization, and gastrointestinal symptom-specific anxiety score. Second, also from the United Kingdom, symptom subgroups in individuals with IBS predicted disease impact and burden.5Black CJ, Ng CE, Goodoory VC, et al. Novel symptom subgroups in individuals with irritable bowel syndrome predict disease impact and burden. Clin Gastroenterol Hepatol. 2023 Feb 27 [E-pub ahead of print].Google Scholar In this analysis, 7 clusters of patients with IBS were identified based on the presence of diarrhea, constipation, gastrointestinal symptoms, and psychological burden. It was demonstrated that high psychological burden was associated with worse quality of life (both IBS specific and generic), as well as with reduced productivity, ability to work, ability to manage affairs at home, engage in social and private leisure activities, and maintain close relationships. Moreover, high psychological burden was associated with higher IBS-related healthcare costs during the prior year, particularly in patients who had a high degree of gastrointestinal symptoms as well as high psychological burden, which were associated with greater than the equivalent of US$1200 per person per year. Third, a study from the Netherlands6Bosman M, Weerts Z, Snijkers JTW, et al. The socioeconomic impact of irritable bowel syndrome: an analysis of direct and indirect health care costs. Clin Gastroenterol Hepatol. 2023 Jan 31 [E-pub ahead of print].Google Scholar documented the socioeconomic impact of IBS including an analysis of direct and indirect healthcare costs. The total quarterly mean cost per IBS patient was estimated to be $2444, with $1354 indirect costs and $909 direct costs. Factors associated with significantly higher costs were age, male sex, unemployment, increased depressive symptoms, reduced IBS quality of life, and IBS subtypes other than constipation-predominant IBS (IBS-C). Current guidelines for the management of IBS stress the importance of symptom-based diagnosis, as with the Rome criteria, followed by guideline-based treatment.7Lembo A. Sultan S. Chang L. et al.AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with diarrhea.Gastroenterology. 2022; 163: 137-151Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,8Chang L. Sultan S. Lembo A. et al.AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with constipation.Gastroenterology. 2022; 163: 118-136Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Given the variation in the iterations of the Rome criteria, as well as multiple deficiencies documented elsewhere9Camilleri M. Irritable bowel syndrome: straightening the road from the Rome criteria.Neurogastroenterol Motil. 2020; 32e13957Crossref Scopus (20) Google Scholar that question the rationale for splitting the different syndromes identified by the criteria such as functional diarrhea and IBS-D, or functional constipation and IBS-C, there has been a plea for simpler identification of the classical symptoms of abdominal pain, bowel dysfunction, and bloating, and exclusion of alarm symptoms in identifying the clinical syndromes. An alternative approach to management is to apply the advances in the application of actionable biomarkers that identify the pathophysiologic mechanisms resulting in the generation of symptoms, followed by individualized therapy directed toward the mechanisms relevant to the individual patient (Figure 1).10Camilleri M. Boeckxstaens G. Irritable bowel syndrome: treatment based on pathophysiology and biomarkers.Gut. 2023; 72: 590-599Crossref PubMed Scopus (8) Google Scholar,11Camilleri M. Chedid V. Actionable biomarkers: the key to resolving disorders of gastrointestinal function.Gut. 2020; 69: 1730-1737Crossref PubMed Scopus (24) Google Scholar The guidance from the American Gastroenterological Association guidelines on the treatment of IBS7Lembo A. Sultan S. Chang L. et al.AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with diarrhea.Gastroenterology. 2022; 163: 137-151Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,8Chang L. Sultan S. Lembo A. et al.AGA Clinical Practice Guideline on the pharmacological management of irritable bowel syndrome with constipation.Gastroenterology. 2022; 163: 118-136Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar is essentially to pursue first the establishment of an optimal provider–patient relationship, education and reassurance, and lifestyle modifications including exercise, sleep, and stress reduction, as well as dietary modifications such as the introduction of fiber supplementation for patients who have constipation. After pursuing these general management strategies, patients with IBS-C are exposed to first- and second-line treatments directed at the constipation and abdominal pain, including osmotic laxatives and antispasmodics as first-line treatment for mild disease, and the introduction of secretagogues for moderate disease. In patients with IBS-D, the therapeutic approaches are treatment with loperamide and an empiric trial of bile acid sequestrant, and the same antispasmodic approach for the abdominal pain. For patients with moderately severe disease, central neuromodulators are applied, particularly tricyclic agents, which also have an anticholinergic function. Alternative therapies for moderate disease include the nonabsorbable antibiotic rifaximin and the agent eluxadoline, which has effects on different opioid receptors. The third-line treatment recommended for IBS-D is alosetron. If abdominal pain and psychological symptoms are persistent, it is recommended that there would be additional focus on brain functions through use of central neuromodulators, as well as brain–gut behavior therapies such as cognitive behavioral therapy or hypnosis. A legitimate question that arises from such guidelines is, how expensive are these approaches for the insurer and the patient? Studies by Shah et al12Shah E.D. Chang L. Salwen-Deremer J.K. et al.Contrasting clinician and insurer perspectives to managing irritable bowel syndrome: multilevel modeling analysis.Am J Gastroenterol. 2021; 116: 748-757Crossref PubMed Scopus (15) Google Scholar, 13Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Comparing costs and outcomes of treatments for irritable bowel syndrome with diarrhea: cost-benefit analysis.Clin Gastroenterol Hepatol. 2022; 20: 136-144.e31Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 14Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Pharmacologic, dietary, and psychological treatments for irritable bowel syndrome with constipation: cost utility analysis.MDM Policy Pract. 2021; 62381468320978417PubMed Google Scholar have addressed several of the relevant questions for each subcategory of IBS. First, from an insurance perspective, starting with global treatments for IBS (central neuromodulators, dietician-directed low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet, and cognitive behavioral therapy) is more cost-saving than starting with on-label prescription drug treatments. In contrast, allowing on-label drugs first while reserving global IBS treatments for those patients who are refractory to the on-label drugs was associated with a total expense of $11,175.63, with an additional expense of $9034.59 in IBS-D compared with untreated IBS-D, and a total expense of $6858.31 and an additional expense of $2972.83 in IBS-C compared with untreated IBS-C.12Shah E.D. Chang L. Salwen-Deremer J.K. et al.Contrasting clinician and insurer perspectives to managing irritable bowel syndrome: multilevel modeling analysis.Am J Gastroenterol. 2021; 116: 748-757Crossref PubMed Scopus (15) Google Scholar Second, from the perspective of calculating a cost-benefit analysis, societal insurer and patient perspectives in both IBS-D and IBS-C have been published13Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Comparing costs and outcomes of treatments for irritable bowel syndrome with diarrhea: cost-benefit analysis.Clin Gastroenterol Hepatol. 2022; 20: 136-144.e31Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar,14Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Pharmacologic, dietary, and psychological treatments for irritable bowel syndrome with constipation: cost utility analysis.MDM Policy Pract. 2021; 62381468320978417PubMed Google Scholar relative to the cost of no treatment. From the patient perspective and assuming approval by the individual patient's insurance, the cost of no treatment for IBS-D was estimated to be $4789.13, with additional costs of treatments such as cognitive behavioral therapy, low FODMAP diet, tricyclic antidepressants, rifaximin, eluxadoline, and alosetron ranging from around $1900 to $2700.13Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Comparing costs and outcomes of treatments for irritable bowel syndrome with diarrhea: cost-benefit analysis.Clin Gastroenterol Hepatol. 2022; 20: 136-144.e31Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Similarly, for IBS-C, the cost of no treatment was estimated to be $5805, and the cost for treatments with linaclotide, lubiprostone, plecanatide, selective serotonin reuptake inhibitor, low FODMAP diet, and cognitive behavioral therapy from the patient perspective ranged from $2800 to $5800 (Table 1).14Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Pharmacologic, dietary, and psychological treatments for irritable bowel syndrome with constipation: cost utility analysis.MDM Policy Pract. 2021; 62381468320978417PubMed Google ScholarTable 1Costs Associated With Different Therapeutic Strategies in Patients With Diarrhea- and Constipation-Predominant Irritable Bowel SyndromeTherapeutic Strategies (Price in US$ per year)Insurer Perspective ($)Patient Perspective ($)ReferenceDiarrhea-predominant irritable bowel syndromeNo treatment2141.054789.1313Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Comparing costs and outcomes of treatments for irritable bowel syndrome with diarrhea: cost-benefit analysis.Clin Gastroenterol Hepatol. 2022; 20: 136-144.e31Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarCBT1808.952734.14Low FODMAP1242.622730.29Alosetron15,708.921868.03Rifaximin6144.532725.92Eluxadoline11,567.001896.02TCA964.072049.97Constipation-predominant irritable bowel syndromeNo treatment3929.375805.0014Shah E.D. Salwen-Deremer J.K. Gibson P.R. et al.Pharmacologic, dietary, and psychological treatments for irritable bowel syndrome with constipation: cost utility analysis.MDM Policy Pract. 2021; 62381468320978417PubMed Google ScholarCBT2129.063275.79Low FODMAP2124.093230.31Lubiprostone7218.004596.04Plecanatide7139.643611.01Linaclotide6460.632822.20SSRI2046.583010.30CBT, cognitive behavioral therapy; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Open table in a new tab CBT, cognitive behavioral therapy; FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. In summary, based on the direct and indirect costs of IBS as well as the cause of prescription medications, it is evident that the sequential application of these pharmacological agents based on tolerance of the medication, absence of adverse effects, and treatment choices based on symptoms of pain diarrhea or constipation involves significant expenditures. It is relevant to emphasize that the commonly used biomarkers are intended predominantly to exclude underlying diseases such as celiac disease or colorectal cancer. A prospective real-life cohort study demonstrated that these biomarkers do not contribute to IBS diagnosis. Thus, among 218 patients with Rome III–positive IBS who were below the age of 50 years and had no red flags such as rectal bleeding or unintentional weight loss evaluated at a center of excellence for IBS patients,15Kramer S. Masclee A.A.M. Jebbink R.J.A. et al.Commonly used biomarkers do not contribute to diagnosing irritable bowel syndrome.Eur J Gastroenterol Hepatol. 2022; 34: 302-307Crossref PubMed Scopus (2) Google Scholar the standard blood and fecal investigations, that is, measurements of hemoglobin, thyroid-stimulating hormone, celiac serology, and fecal calprotectin, during the first consultation contributed minimally to the diagnosis of patients who were followed for at least 1 year. Among these patients, 47 also underwent colonoscopy, and the final diagnoses were 210 IBS, 5 inflammatory bowel disease, 1 nonspecific ileitis, 1 hyperthyroidism, and 1 celiac disease. It was estimated that there were costs of €4900 to diagnose 1 patient with a diagnosis other than IBS.15Kramer S. Masclee A.A.M. Jebbink R.J.A. et al.Commonly used biomarkers do not contribute to diagnosing irritable bowel syndrome.Eur J Gastroenterol Hepatol. 2022; 34: 302-307Crossref PubMed Scopus (2) Google Scholar In prior studies,11Camilleri M. Chedid V. Actionable biomarkers: the key to resolving disorders of gastrointestinal function.Gut. 2020; 69: 1730-1737Crossref PubMed Scopus (24) Google Scholar we documented the sensitivity, specificity, predictive values, and positive and negative likelihood ratios based on established cutoff values for rectal evacuation disorder, fast or slow colonic transit, bile acid diarrhea, and carbohydrate maldigestion. The specific tests are documented in Table 2.16Brandler J. Camilleri M. Pretest and post-test probabilities of diagnoses of rectal evacuation disorders based on symptoms, rectal exam, and basic tests: a systematic review.Clin Gastroenterol Hepatol. 2020; 18: 2479-2490Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 17Heinrich H. Sauter M. Fox M. et al.Assessment of obstructive defecation by high-resolution anorectal manometry compared with magnetic resonance defecography.Clin Gastroenterol Hepatol. 2015; 13: 1310-1317.e1Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 18Chedid V. Vijayvargiya P. Halawi H. et al.Audit of the diagnosis of rectal evacuation disorders in chronic constipation.Neurogastroenterol Motil. 2019; 31e13510Crossref Scopus (24) Google Scholar, 19Park S.Y. Khemani D. Acosta A. et al.Rectal gas volume: Defining cut-offs for screening for evacuation disorders in patients with constipation.Neurogastroenterol Motil. 2017; 29https://doi.org/10.1111/nmo.13044Crossref Scopus (11) Google Scholar, 20Cangemi D.J. Flanagan R. Barshop K. et al.Colonic stool burden a useful surrogate for slow transit constipation as determined by a radiopaque transit study.Am J Gastroenterol. 2019; 114: 519-523Crossref PubMed Scopus (14) Google Scholar, 21Nullens S. Nelsen T. Camilleri M. et al.Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation.Gut. 2012; 61: 1132-1139Crossref PubMed Scopus (82) Google Scholar, 22Manabe N. Wong B.S. Camilleri M. et al.Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort.Neurogastroenterol Motil. 2010; 22: 293-e82Crossref PubMed Scopus (113) Google Scholar, 23Sciarretta G. Furno A. Mazzoni M. et al.Post-cholecystectomy diarrhea: evidence of bile acid malabsorption assessed by SeHCAT test.Am J Gastroenterol. 1992; 87: 1852-1854PubMed Google Scholar, 24Camilleri M. Acosta A. Busciglio I. et al.Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther. 2015; 41: 438-448Crossref PubMed Scopus (92) Google Scholar, 25Vijayvargiya P. Camilleri M. Carlson P. et al.Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea.Aliment Pharmacol Ther. 2017; 46: 581-588Crossref PubMed Scopus (52) Google Scholar, 26Götze H. Mahdi A. [Fructose malabsorption and dysfunctional gastrointestinal manifestations].Monatsschr Kinderheilkd. 1992; 140: 814-817PubMed Google Scholar, 27Rosado J.L. Solomons N.W. Sensitivity and specificity of the hydrogen breath-analysis test for detecting malabsorption of physiological doses of lactose.Clin Chem. 1983; 29: 545-548Crossref PubMed Scopus (59) Google Scholar, 28Thomforde G.M. Camilleri M. Phillips S.F. et al.Evaluation of an inexpensive screening scintigraphic test of gastric emptying.J Nucl Med. 1995; 36: 93-96PubMed Google Scholar, 29Kim D.Y. Delgado-Aros S. Camilleri M. et al.Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia.Am J Gastroenterol. 2001; 96: 3099-3105Crossref PubMed Google ScholarTable 2Performance Characteristics Based on Established Cutoff Values for Rectal Evacuation Disorder, Fast or Slow Colonic Transit, BA Diarrhea, and Carbohydrate MaldigestionaData reproduced with permission from Camilleri and Chedid.11 and Average Costs of Different Biomarkers in Selected Cities in the United States Obtained From a Publicly Available Website and Including Facility FeesBiomarkerCutoffsSn (%)Sp (%)PPV (%)NPV (%)+LR–LRReferenceCPTMedian Charge (US$)Rectal evacuation disordersDRE>2 findings on DRE83.968.14992.82.60.216Brandler J. Camilleri M. Pretest and post-test probabilities of diagnoses of rectal evacuation disorders based on symptoms, rectal exam, and basic tests: a systematic review.Clin Gastroenterol Hepatol. 2020; 18: 2479-2490Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarAnorectal manometry: rectoanal pressure gradient<–40 mm Hg32.410010085.5>100.717Heinrich H. Sauter M. Fox M. et al.Assessment of obstructive defecation by high-resolution anorectal manometry compared with magnetic resonance defecography.Clin Gastroenterol Hepatol. 2015; 13: 1310-1317.e1Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar911221194.5Balloon expulsion test22 s77.869.839.292.62.60.318Chedid V. Vijayvargiya P. Halawi H. et al.Audit of the diagnosis of rectal evacuation disorders in chronic constipation.Neurogastroenterol Motil. 2019; 31e13510Crossref Scopus (24) Google ScholarRectal gas volume>20 mL38.189.146.685.23.50.719Park S.Y. Khemani D. Acosta A. et al.Rectal gas volume: Defining cut-offs for screening for evacuation disorders in patients with constipation.Neurogastroenterol Motil. 2017; 29https://doi.org/10.1111/nmo.13044Crossref Scopus (11) Google ScholarRectal area on scout film>900 mm239.573.827.483.01.50.819Park S.Y. Khemani D. Acosta A. et al.Rectal gas volume: Defining cut-offs for screening for evacuation disorders in patients with constipation.Neurogastroenterol Motil. 2017; 29https://doi.org/10.1111/nmo.13044Crossref Scopus (11) Google Scholar74018294.5Slow transit constipationStool burden score on abdominal x-ray>786.954.527.195.51.90.220Cangemi D.J. Flanagan R. Barshop K. et al.Colonic stool burden a useful surrogate for slow transit constipation as determined by a radiopaque transit study.Am J Gastroenterol. 2019; 114: 519-523Crossref PubMed Scopus (14) Google Scholar74018294.5Colonic transit with scintigraphy: GCGC 48 h <2.1826531.394.92.40.321Nullens S. Nelsen T. Camilleri M. et al.Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation.Gut. 2012; 61: 1132-1139Crossref PubMed Scopus (82) Google Scholar782662256.5Fast transit diarrheaColonic transit with scintigraphyGC 24 h >3.831.687.221.591.92.50.822Manabe N. Wong B.S. Camilleri M. et al.Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort.Neurogastroenterol Motil. 2010; 22: 293-e82Crossref PubMed Scopus (113) Google Scholar782662256.5Bile acid diarrhea75SeHCAT retention3-d 34%1009433771.70.923Sciarretta G. Furno A. Mazzoni M. et al.Post-cholecystectomy diarrhea: evidence of bile acid malabsorption assessed by SeHCAT test.Am J Gastroenterol. 1992; 87: 1852-1854PubMed Google Scholar48-h fecal BA1° BA >4% + total BA >1000 μmol469783.684.315.35.124Camilleri M. Acosta A. Busciglio I. et al.Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome.Aliment Pharmacol Ther. 2015; 41: 438-448Crossref PubMed Scopus (92) Google Scholar82239102FGF-19≤61.7 pg/mL298329781.30.925Vijayvargiya P. Camilleri M. Carlson P. et al.Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea.Aliment Pharmacol Ther. 2017; 46: 581-588Crossref PubMed Scopus (52) Google Scholar7αC4≥52.5 ng/mL297833791.70.825Vijayvargiya P. Camilleri M. Carlson P. et al.Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea.Aliment Pharmacol Ther. 2017; 46: 581-588Crossref PubMed Scopus (52) Google Scholar82542163Carbohydrate maldigestionFructose breath testPeak rise in breath H2 >20 ppm988626.999.97.00.0226Götze H. Mahdi A. [Fructose malabsorption and dysfunctional gastrointestinal manifestations].Monatsschr Kinderheilkd. 1992; 140: 814-817PubMed Google Scholar91065668.5Lactose breath testPeak rise in breath H2 >20 μL/L8010010098.9∞0.227Rosado J.L. Solomons N.W. Sensitivity and specificity of the hydrogen breath-analysis test for detecting malabsorption of physiological doses of lactose.Clin Chem. 1983; 29: 545-548Crossref PubMed Scopus (59) Google Scholar91065668.5Upper GI motor dysfunctionsGastric emptying of solids at 4 h with scintigraphy>25% retention100706.41003.3028Thomforde G.M. Camilleri M. Phillips S.F. et al.Evaluation of an inexpensive screening scintigraphic test of gastric emptying.J Nucl Med. 1995; 36: 93-96PubMed Google ScholarGastric accommodation with SPECTAccommodation ratio >3.040.69552.592.18.10.629Kim D.Y. Delgado-Aros S. Camilleri M. et al.Noninvasive measurement of gastric accommodation in patients with idiopathic nonulcer dyspepsia.Am J Gastroenterol. 2001; 96: 3099-3105Crossref PubMed Google ScholarData are from New York, NY; Los Angeles, CA; Chicago, IL; Miami, FL; Dallas, TX; Omaha, NE; St Louis, MO; and Birmingham, AL, and from https://www.fairhealthconsumer.org/.BA, bile acid; CPT, Current Procedural Terminology; DRE, digital rectal exam; GC, geometric center; GI, gastrointestinal; NPV, negative predictive value; PPV, positive predictive value; Sn, sensitivity; Sp, specificity; SPECT, single-photon emission computed tomography; +LR, positive likelihood ratio; –LR, negative likelihood ratio.a Data reproduced with permission from Camilleri and Chedid.11Camilleri M. Chedid V. Actionable biomarkers: the key to resolving disorders of gastrointestinal function.Gut. 2020; 69: 1730-1737Crossref PubMed Scopus (24) Google Scholar Open table in a new tab Data are from New York, NY; Los Angeles, CA; Chicago, IL; Miami, FL; Dallas, TX; Omaha, NE; St Louis, MO; and Birmingham, AL, and from https://www.fairhealthconsumer.org/. BA, bile acid; CPT, Current Procedural Terminology; DRE, digital rectal exam; GC, geometric center; GI, gastrointestinal; NPV, negative predictive value; PPV, positive predictive value; Sn, sensitivity; Sp, specificity; SPECT, single-photon emission computed tomography; +LR, positive likelihood ratio; –LR, negative likelihood ratio. Colonic transit could also be measured noninvasively with radiopaque markers30Metcalf A.M. Phillips S.F. Zinsmeister A.R. et al.Simplified assessment of segmental colonic transit.Gastroenterology. 1987; 92: 40-47Abstract Full Text PDF PubMed Scopus (805) Google Scholar or wireless capsule, both of which are generally available.31Rao S.S. Kuo B. McCallum R.W. et al.Investigation of colonic and whole-gut transit with wireless motility capsule and radiopaque markers in constipation.Clin Gastroenterol Hepatol. 2009; 7: 537-544Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar,32Camilleri M. Thorne N.K. Ringel Y. et al.Wireless pH-motility capsule for colonic transit: prospective comparison with radiopaque markers in chronic constipation.Neurogastroenterol Motil. 2010; 22: 874-882.e233Crossref PubMed Scopus (160) Google Scholar In general, these methods have been validated more extensively in patients with constipation, rather than in patients with chronic diarrhea. However, there are published data showing that radiopaque markers can also detect abnormal transit in diarrhea as well as in constipation.33Sadik R. Stotzer P.O. Simrén M. et al.Gastrointestinal transit abnormalities are frequently detected in patients with unexplained GI symptoms at a tertiary centre.Neurogastroenterol Motil. 2008; 20: 197-205Crossref PubMed Scopus (65) Google Scholar In patients with chronic diarrhea, accelerated transit through the colon can be accurately measured with scintigraphy, which may not be generally available. For example, the location of isotope in the colon at 36 hours is significantly greater in the descending colon, sigmoid colon, and rectum and in stool compared with healthy volunteers.34Vassallo M. Camilleri M. Phillips S.F. et al.Transit through the proximal colon influences stool weight in the irritable bowel syndrome.Gastroenterology. 1992; 102: 102-108Crossref PubMed Scopus (193) Google Scholar Indeed, the colonic geometric center at 24 hours >3.8 (in which 0 represents the ileocecal valve and 5 represents 100% of the isotope in stool) had a specificity of 87.2% to identify rapid-transit diarrhea.22Manabe N. Wong B.S. Camilleri M. et al.Lower functional gastrointestinal disorders: evidence of abnormal colonic transit in a 287 patient cohort.Neurogastroenterol Motil. 2010; 22: 293-e82Crossref PubMed Scopus (113) Google Scholar Analysis of colonic transit at 48 hours by scintigraphy has also been shown to differentiate the colonic transit profile of patients with evacuation disorder compared with that of patients with slow transit constipation.21Nullens S. Nelsen T. Camilleri M. et al.Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation.Gut. 2012; 61: 1132-1139Crossref PubMed Scopus (82) Google Scholar Identification of accelerated or delayed transit provides an opportunity to institute treatment with medications such as new opioid agonists or 5-HT3 antagonists for rapid transit, and chloride secretagogues (lubiprostone, linaclotide, plecanatide), inhibitors of sodium absorption (tenapanor), or 5-HT4 agonists for slow colonic transit (Table 3). Indeed, it has be